Process for the Preparation of 4-(Benzimidazolylmethylamino)-Benzamides and the Salts Thereof

ABSTRACT

The invention relates to a process for preparing an optionally substituted 4-benzimidazol-2-ylmethylamino)-benzamidine, characterised in that (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, (b) i) the product thus obtained is hydrogenated and ii) optionally the amidino group is carbonylated, without isolating the intermediate product of the hydrogenation beforehand; as well as a process for preparing a salt of an optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine, wherein (a) an optionally correspondingly substituted diaminobenzene is condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, (b) the product thus obtained is hydrogenated, and (c) i) optionally the amidino group is carbonylated and ii) without prior isolation of the intermediate product of the carbonylation the desired salt is isolated.

RELATED APPLICATIONS

This application claims priority to German Application DE 10 2005 061623.2 filed Dec. 21, 2005, which is hereby incorporated by reference.

BACKGROUND TO THE INVENTION

1. Technical Field

The invention relates to a process for preparing an optionallysubstituted 4-(benzimidazol-2-ylmethylamino)-benzamidine, wherein

-   (a) an optionally correspondingly substituted diaminobenzene is    condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic    acid and-   (b) i) the product thus obtained is hydrogenated and    -   ii) optionally the amidino group is carbonylated without        isolating the intermediate product of the hydrogenation        beforehand.

The 4-(benzimidazol-2-ylmethylamino)-benzamidine thus obtained maysubsequently be converted into a salt.

Moreover, the invention relates to a process for preparing a salt of anoptionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidine,wherein

-   (a) an optionally correspondingly substituted diaminobenzene is    condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic    acid,-   (b) the product thus obtained is hydrogenated, and-   (c) i) optionally the amidino group is carbonylated and    -   ii) without prior isolation of the intermediate product of the        carbonylation the desired salt is isolated.

2. Prior Art

Substituted (4-benzimidazol-2-ylmethylamino)-benzamidines, particularly1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide are already knownfrom International Patent Application WO 98/37075 as active substanceswith a thrombin-inhibiting and thrombin time prolonging activity.

The main types of indication for the compound of chemical formula I arethe postoperative prevention of deep vein thrombosis and the preventionof stroke (prevention of stroke due to atrial fibrillation, SPAF forshort).

In WO 98/37075 it is proposed that the substituted(4-benzimidazol-2-ylmethylamino)-benzamidines be prepared by reactingthe corresponding substituted(4-benzimidazol-2-ylmethylamino)-benzonitriles with ammonia. Thisprocess is highly complex from the point of view of productiontechnology and results in a high loading of acids that have to bedisposed of.

The aim of the present invention was to indicate an alternative methodof preparing the substituted(4-benzimidazol-2-ylmethylamino)-benzamidines, by which thistechnologically complex step could be avoided.

BRIEF SUMMARY OF THE INVENTION

Surprisingly it has now been found that the substituted4-(benzimidazol-2-ylmethylamino)-benzamidines can be produced in highyields and using inexpensive adjuvants if

-   (a) an optionally correspondingly substituted diaminobenzene is    condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic    acid and-   (b) i) the product thus obtained is hydrogenated, and    -   ii) optionally the amidino group is carbonylated, preferably        with an alkyl halogen formate in the presence of a base,        particularly with n-hexylchloroformate, without isolating the        intermediate product of the hydrogenation beforehand.

The 4-(benzimidazol-2-ylmethylamino)-benzamidine thus obtained maysubsequently be converted into a salt.

It has also surprisingly been found that the salts of optionallysubstituted 4-(benzimidazol-2-ylmethylamino)-benzamidines can beprepared in high yields and using inexpensive adjuvants if

-   (a) an optionally correspondingly substituted diaminobenzene is    condensed with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic    acid,-   (b) the product thus obtained is hydrogenated, and-   (c) i) optionally the amidino group is carbonylated and    -   ii) without prior isolation of the intermediate product of the        carbonylation the desired salt is isolated.

DETAILED DESCRIPTION OF THE INVENTION

A process for preparing an optionally substituted4-(benzimidazol-2-ylmethylamino)-benzamidine of formula (I) is preferred

wherein

-   R¹ denotes a C₁₋₆-alkyl or C₃₋₇-cycloalkyl group,-   R²-   (i) denotes a C₁₋₆-alkyl group, a C₃₋₇-cycloalkyl group optionally    substituted by a C₁₋₃-alkyl group, while the C₁₋₃-alkyl group may    additionally be substituted by a carboxyl group or by a group which    may be converted in vivo into a carboxy group, or-   (ii) denotes an R²¹NR²² group, wherein    -   R²¹ denotes a C₁₋₆ alkyl group which may be substituted by a        carboxy, C₁₋₆ alkoxycarbonyl, benzyloxycarbonyl,        C₁₋₃-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl,        trifluorosulphonylamino, trifluorosulphonylaminocarbonyl or        1H-tetrazolyl group, a C₂₋₄-alkyl group substituted by a        hydroxy, phenyl-C₁₋₃-alkoxy, carboxy-C₁₋₃-alkylamino,        C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylamino,        N-(C₁₋₃-alkyl)-carboxy-C₁₋₃-alkylamino or        N-(C₁₋₃-alkyl)-C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylamino group, while        in the above-mentioned groups the carbon atom in the α-position        to the adjacent nitrogen atom cannot be substituted, or    -   a piperidinyl group optionally substituted by a C₁₋₃-alkyl        group, and R²² denotes a hydrogen atom, a C₁₋₆-alkyl group, a        C₃₋₇-cycloalkyl group optionally substituted by a C₁₋₃-alkyl        group, or a C₃₋₆-alkenyl or C₃₋₆-alkynyl group, while the        unsaturated moiety may not be linked directly to the nitrogen        atom of the R²¹NR²² group, a phenyl group optionally substituted        by a fluorine, chlorine or bromine atom, by a C₁₋₃-alkyl or        C₁₋₃-alkoxy group, or a benzyl, oxazolyl, isoxazolyl, thiazolyl,        isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,        pyridazinyl, pyrrolyl, thienyl or imidazolyl group optionally        substituted by a C₁₋₃-alkyl group, or R²¹ and R²² together with        the nitrogen atom between them denote a 5- to 7-membered        cycloalkyleneimino group optionally substituted by a carboxy or        C₁₋₄-alkoxycarbonyl group, to which additionally a phenyl ring        may be fused, and-   R³ denotes a hydrogen atom, a C₁₋₉-alkoxycarbonyl,    cyclohexyloxycarbonyl, phenyl-C₁₋₃-alkoxycarbonyl, benzoyl,    p-C₁₋₃-alkyl-benzoyl or pyridinoyl group, wherein the ethoxy moiety    in the 2 position of the above-mentioned C₁₋₉-alkoxycarbonyl group    may additionally be substituted by a C₁₋₃-alkylsulphonyl or    2-(C₁₋₃-alkoxy)-ethyl group, while in step (a) a phenyldiamine of    formula (II)-    wherein R¹ and R² have the meanings given for formula (I),-   is reacted with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic    acid, the resulting product of formula (III)-    wherein R¹ and R² have the meanings given for formula (I),-   is hydrogenated in step (b)i), and subsequently, without any prior    isolation of the hydrogenation product, the compound of formula (I)    thus obtained wherein R³ denotes hydrogen is optionally reacted in    step (b)ii) with a compound of formula (IV)    R³—X  (IV)-    wherein R³ has the meaning given for formula (I), and-   X denotes a suitable leaving group.

The 4-(benzimidazol-2-ylmethylamino)-benzamidine thus obtained may ifdesired subsequently be converted into a salt, particularly into apharmaceutically acceptable salt, in another step (c).

Another preferred process for preparing a salt of an optionallysubstituted 4-(benzimidazol-2-ylmethylamino)-benzamidine of formula (I)

wherein R¹ to R³ are as hereinbefore defined, comprises the followingsteps:

-   (a) reacting a phenyldiamine of formula (II)-    wherein R¹ and R² have the meanings given for formula (I),-   with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid,-   (b) hydrogenating the product of formula (III) thus obtained-    wherein R¹ and R² have the meanings given for formula (I), and-   (c) i) reacting the compound of formula (I) thus obtained wherein    R³denotes hydrogen with a compound of formula (IV)    R³—X  (IV)-    wherein R ³ has the meaning given for formula (I) and-   X denotes a suitable leaving group, and-   ii) precipitating the desired salt of the compound of formula (I)    thus obtained, without previously isolating the carbonylation    product.

Particularly preferred are the processes according to the invention forpreparing the compounds of formula (I) or the salts thereof, wherein

-   R¹ denotes a C₁₋₃-alkyl group,-   R² denotes an R²¹NR²² group, wherein    -   R²¹ denotes a C₁₋₃ alkyl group which may be substituted by a        carboxy, C₁₋₃ alkoxycarbonyl, and    -   R²² denotes a hydrogen atom, a C₁₋₃-alkyl group, a pyridinyl        group optionally substituted by a C₁₋₃-alkyl group, and-   R³ denotes a hydrogen atom, a C₁₋₈-alkoxycarbonyl group.

Most preferred are the processes according to the invention forpreparing the compound of formula (I) or the salts thereof, wherein

-   R¹ denotes a methyl group,-   R² denotes an R²¹NR²² group, wherein    -   R²¹ denotes an ethyl group which is substituted by an        ethoxycarbonyl group, and    -   R²² denotes a pyridin-2-yl group, and-   R³ denotes an n-hexyloxycarbonyl group.

Preferred salts are the methanesulphonate, chloride, maleate, tartrate,salicylate, citrate and malonate of the compound of formula (I). Aparticularly preferred salt is the methanesulphonate.

The following embodiments (A) to (F) of the process according to theinvention are preferred:

(A) The condensation of step (a) is carried out in the presence of aninert diluent and a water-binding agent.

The correspondingly substituted diaminobenzenes of formula (II) areknown e.g. from International Patent Application WO 98/37075, e.g. fromExample 25 (Steps a and b), or may be prepared analogously to thosedescribed therein. For the hydrogenation of the nitro precursor compoundfor preparing the diaminobenzene of formula (II) the solvent used maybe, for example, toluene, isopropanol, triethylamine, ethanol, butylacetate, ethyl acetate, methanol or mixtures of these solvents.Preferably, the hydrogenation is carried out under a hydrogen pressureof 1 to 20 bar, but higher pressures are also possible. Theconcentration of the aromatic nitrogen compound (educt) is conveniently10 to 40 wt. %; it is more preferably present in a concentration of 20to 30 wt. %. The catalyst used may be for example 5-10% palladium oncharcoal, while preferably 2-20 wt. % of wet charcoal-palladium catalystis used, based on the aromatic nitrogen compound, which corresponds toabout 0.05-1 wt. % palladium based on the aromatic nitrogen compound.Particularly preferably, 3-amino-4-methylaminobenzoic acid amides areused, particularly 3-amino-4-methylaminobenzoicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide.

The inert diluents used may be both aprotic apolar solvents—such as e.g.aliphatic or aromatic, optionally halogenated hydrocarbons—or aproticpolar solvents such as e.g. ethers and/or amides or lactams and/ormixtures thereof. The aprotic apolar solvents used are preferablybranched or unbranched C₅-C₈ aliphatic alkanes, C₄-C₁₀ cycloalkanes,C₁-C₆ aliphatic haloalkanes, C₆-C₁₀ aromatic alkanes or mixturesthereof. It is particularly preferable to use alkanes such as pentane,hexane or heptane, cycloalkanes such as cyclohexane ormethylcyclohexane, haloalkanes such as dichloromethane, aromatic alkanessuch as benzene, toluene or xylene or mixtures thereof Suitable aproticsolvents are polar ethers such as, for example, tetrahydrofuran (THF),methyltetrahydrofuran, dioxane, tert-butyl-methylether ordimethoxyethylether or amides such as, for example, dimethylformamide,or lactams such as N-methylpyrrolidone, for example.

Water-binding agents which may be used are hygroscopic salts, inorganicor organic acids or the acid chlorides thereof, anhydrides of inorganicor organic acids, anhydrides of alkanephosphonic acids, molecular sievesor urea derivatives. 1,1′-carbonyldiimidazoles and alkanephosphonicanhydrides are preferred, while alkanephosphonic anhydrides areparticularly preferred.

In a preferred embodiment 1,1′-carbonyldiimidazole is suspended in THFand heated. 2-[4-(1,2,4-Oxadiazol-5-on-3-yl)-phenylamino]-acetic acid isadded. The correspondingly substituted diaminobenzene is added to THF.The reaction mixture is stirred at about 50° C. and subsequently, afterthe addition of acetic acid, evaporated down and mixed with water andthe solid substance is filtered off, washed and dried.

In a second particularly preferred embodiment, alkanephosphonicanhydrides are added, in the presence of an organic base, preferably atert. amine such as e.g. DIPEA, to a solution of2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid andcorrespondingly substituted diaminobenzene in THF. The reaction mixtureis stirred, preferably at temperatures between −10 and 50° C., andsubsequently, after the addition of acetic acid, evaporated down. It iscombined with ethanol/water and optionally a filter aid, for examplekieselguhr (e.g. Clarcel®), and filtered hot. Then the substanceprecipitated from the cooled solution is filtered off, washed and dried.

(B) The hydrogenation of step (b)i) or (b) is carried out in thepresence of an inert diluent and a hydrogenation catalyst.

Particularly preferred is a process in which the hydrogenation iscarried out in a temperature range from 0° C. to 100° C., preferablyfrom 15° C. to 75° C., particularly from 30° C. to 60° C.

Also preferred is a process wherein the hydrogenation is carried outunder a pressure of more than 0.5 bar to 100 bar, preferably under apressure of 1 bar to 10 bar, particularly at about 1-4 bar.

The inert diluents may be both protic solvents—such as e.g. alcohols,carboxylic acids and/or water, or aprotic polar solvents such as e.g.ethers and/or amides or lactams and/or mixtures thereof. Water mayoptionally be added to all the solvents. The protic solvents used arepreferably branched or unbranched C₁-C₈ alkanols, C₁-C₃ carboxylic acidsor mixtures thereof Particularly preferably, lower alcohols such asmethanol, ethanol, n-propanol and isopropanol, carboxylic acids such asformic acid, acetic acid and propionic acid or mixtures thereof areused. It is particularly preferably to use as the reaction mediumethanol and/or acetic acid, which may optionally contain water. Suitableaprotic solvents include polar ethers such as for exampletetrahydrofuran, dioxane or dimethoxyethylether or amides such as forexample dimethylformamide, or lactams such as for exampleN-methylpyrrolidone. Preferably, solvents with a low tendency toflammability are used.

Suitable hydrogenation catalysts are generally transition metals such asfor example nickel, platinum or palladium or the salts or oxides thereofRaney nickel, platinum oxide and palladium on an inert carrier material,particularly palladium on activated charcoal (Pd/C) are preferred.

Processes in which the product of step (a) is used in a ratio by weightto the hydrogenation catalyst of 1:1 to 1000:1, preferably from 5:1 to100:1 during hydrogenation are preferred.

In a preferred embodiment of step (b) the product of step (a) is takenup in ethanol and after the addition of acetic acid and at 2 barhydrogen it is hydrogenated with water-moistened 10% Pd/C at ambienttemperature. The catalyst is filtered off and p-toluenesulphonic acid,dissolved in 90 ml of ethanol or in 90 ml of water, is added. Preferablyan aqueous p-toluenesulphonic acid solution is used. The tosylate of the4-(benzimidazol-2-ylmethylamino)-benzamidine obtained is precipitated,filtered off and washed with ethanol in several batches.

In a particularly preferred embodiment of step (b) the product of step(a) is taken up in ethanol/water and at 4 bar hydrogen hydrogenated withwater-moistened 10% Pd/C at 60° C. The catalyst is filtered off andp-toluenesulphonic acid (solid or dissolved in 90 ml of ethanol or in 90ml of water) is added. Preferably, solid p-toluenesulphonic acid isused. The tosylate of the 4-(benzimidazol-2-ylmethylamino)-benzamidineobtained is precipitated, filtered off and washed with ethanol inseveral batches.

In a preferred embodiment of step (b)i) the product of step (a) is takenup in a mixture of THF and water (approx. 7:3 based on the volume) andhydrogenated at 4 bar hydrogen with water-moistened 10% Pd/C at approx.40° C. The hydrogenating solution is filtered and the filter is washedwith THF/water (7:3). The filtrate is diluted with THF and water andcombined with potassium carbonate.

Then, according to one variant of the process, the carbonylation in step(b)ii) may be carried out directly. To do this, after separation of thecatalyst without intermediate isolation of the hydrogenation product,the filtrate is combined with an auxiliary base and reacted with acarbonylation agent. The carbonylation agents and bases which may beused as well as possible solvents and suitable temperature ranges aredescribed in more detail under (E). The reaction is preferably carriedout with potassium carbonate and at temperatures between 10-50° C.,preferably 10-20° C.

After the reaction has ended the suspension is heated to approx. 50° C.,for example, so that a clear two-phase mixture is formed. The lower,aqueous phase has a high inorganic load and can be separated off beforethe THF is distilled off and the solvent is exchanged for acetone, fromwhich the compound of formula (I) is crystallised by the addition ofwater.

Possible Variant of the Working Up:

In a variant of the reaction, after the separation of the inorganicallyloaded aqueous phase and distillation of THF, the solvent may beexchanged for butyl acetate. The crystallisation of the compound offormula (I) is then carried out after aqueous extraction of the organicphase and azeotropic elimination of the residual moisture.

(C) In order to prepare2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid,2-[4-(1,2,4-oxadiazol-5-on-3-yl)-aniline is reacted with a 2-haloaceticacid ester, preferably ethyl bromoacetate, in the presence of a weakbase, preferably a tertiary amine, such as for example triethylamine oran alkali metal carbonate, such as for example sodium carbonate in aninert solvent, and the2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid ester obtainedis saponified.

The inert diluents used may be both protic solvents—such as e.g.alcohols, and/or water—or aprotic polar solvents such as e.g. ethersand/or amides or lactams and/or mixtures thereof Water may optionally beadded to all the solvents. Protic solvents used are preferably water orbranched or unbranched C₁-C₈ alkanols or mixtures thereof Particularlypreferably, water or lower alcohols such as methanol, ethanol,n-propanol and isopropanol or mixtures thereof are used. Mostparticularly preferably, ethanol is used as reaction medium, and thismay optionally contain water. Isopropanol, optionally together withwater, may also be used. The most suitable solvent is water, however.Suitable aprotic solvents are polar ethers such as for exampletetrahydrofuran or dimethoxy-ethylether or amides such as for exampledimethylformamide, or lactams such as for example N-methylpyrrolidone.

In a particularly preferred embodiment ethyl bromoacetate is meteredinto a suspension of 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-aniline and sodiumcarbonate in water/isopropanol or preferably in water/ethanol andstirred at 35-45° C. The cooled suspension is suction filtered, washedwith water and ethanol in several batches and dried.

The saponification is preferably carried out in a protic solvent with analkali metal or alkaline earth metal hydroxide, particularly withlithium, sodium or potassium hydroxide.

In a particularly preferred embodiment2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid ester issuspended in water or preferably in water/ethanol and slowly combinedwith an aqueous solution of NaOH at ambient temperature. The suspensionchanges into a solution and is heated to 45 to 75° C. HCl is added tothe solution thus obtained until a pH of about 5 or preferably pH 3 isachieved. The solid is isolated and washed with cold water and coldethanol and MtBE.

(D) In order to prepare 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-aniline,4-aminophenyl-amidoxime is reacted with a dialkyl carbonate, preferablydimethyl carbonate or diethyl carbonate in the presence of a base,preferably an alkali metal alkoxide, particularly sodium methoxide,sodium ethoxide or potassium tert-butoxide.

4-aminophenyl-amidoxime may be prepared e.g. by reacting4-aminobenzonitrile with hydroxylamine hydrochloride.

In a particularly preferred embodiment sodium methoxide or preferablysodium ethoxide is added at 65-75° C., preferably at 70-75° C., to asuspension of 4-aminophenyl-amidoxime in ethanol and rinsed withethanol. After 15 min stirring diethyl carbonate or preferably dimethylcarbonate is added dropwise. After 2-4 hours reaction time the mixtureis cooled and ethanol is distilled off at 120 mbar and 40° C. Theresidue is taken up in water and after heating adjusted to pH 10-12using semi-conc. sodium hydroxide solution, then to pH<6, preferably topH<4, particularly preferably to pH 2-3, by acidifying with conc.hydrochloric acid, and slowly cooled. The solution changes into asuspension, which is filtered and washed several times with cold waterand ethanol.

(E) In order to prepare a salt of a compound of formula (I), wherein R³has a meaning other than hydrogen, by carbonylation of a compound offormula (I), wherein R³ denotes hydrogen, and precipitation of thedesired salt without prior isolation of the carbonylation product, in afirst partial step (c)i) the compound of formula (I), wherein R³ denoteshydrogen, is reacted with a carbonylation agent R³—X, where R³ has themeanings given above, with the exception of hydrogen, and X denotes aleaving group. Preferably X may represent a halogen such as for examplechlorine or bromine or a p-toluenesulphonyl, methanesulphonyl ortrifluoromethanesulphonyl group. Most particularly preferred isn-hexylchloroformate for preparing a compound of formula (I) wherein R³denotes n-hexyl. The reaction is preferably carried out at a temperatureof 10 to 50° C., in particular at 10 to 20° C. in the presence of abase. The base used may conveniently be an alkali metal carbonate suchas for example potassium carbonate or sodium carbonate, an alkali metalhydrogen carbonate such as for example sodium hydrogen carbonate orpotassium hydrogen carbonate or a tertiary amine such as for exampletriethylamine. Preferably potassium carbonate is used. The reaction mayfor example be carried out in mixtures of water and acetone or water andTHF; a water/acetone mixture is preferred.

After the reaction has ended a clear two-phase mixture may be formed byheating the suspension, e.g. to approx. 50° C., so that the aqueousphase, which contains a large proportion of the inorganic constituents,can easily be separated off.

Then a change of solvent may take place. Suitable solvents include forexample ketones or esters such as MIBK, butyl acetate, ethyl acetate,propyl acetate, isopropyl acetate or isobutyl acetate. Particularlypreferred are MIBK and butyl acetate. The organic phase is washed underaqueous conditions, to eliminate polar impurities. Any residual moistureremaining is subsequently removed by azeotropic distillation before theproduct is crystallised and isolated or e.g. combined with acetone forthe partial step c)ii), however, without intermediate isolation andthen, by the addition of the corresponding acid, for examplemethanesulphonic acid, for preparing the methanesulphonate, the desiredsalt is precipitated and isolated directly.

(F) In order to precipitate a specific salt starting from the compoundof formula (I) a solution of the compound of formula (I) is optionallyprepared with heating and then the corresponding acid is added,optionally as a solution. In order to crystallise the salt the mixturemay be cooled. Then the salt is isolated. Suitable solvents include forexample acetone or a mixture of acetone and ethanol.

Optionally the amount of solvent used for preparing the substratesolution may be increased. This allows clear filtration of the solutionbefore the addition of the acid.

The preparation of the2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid needed asintermediate product from 4-aminobenzonitrile is illustrated in thefollowing reaction plan:

The preparation of a 4-(benzimidazol-2-ylmethylamino)-benzamidine isshown by way of example in the following reaction plan:

The working up of the individual reactions may take place in theconventional manner, for example, by separating off the reactionadjuvants, eliminating the solvent and isolating pure end product fromthe residue by crystallisation, distillation, extraction orchromatography.

Following the process described above the compound of formula (I) thusobtained may be converted into a physiologically acceptable salt. Thephysiologically acceptable salts may be salts with inorganic or organicacids or, if the compound contains a carboxy group, with inorganic ororganic bases. Examples of acids for this purpose includemethanesulphonic acid, hydrochloric acid, hydrobromic acid, sulphuricacid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citricacid, tartaric acid or maleic acid. Examples of bases which may be usedinclude sodium hydroxide, potassium hydroxide, cyclohexylamine,ethanolamine, diethanolamine and triethanolamine. The compound offormula (6) is preferably converted into its mesylate.

The process according to the invention will now be illustrated by meansof the following Examples. The skilled man is aware that the Examplesserve only as an illustration and are not to be regarded as restrictive.

EXAMPLES

The following abbreviations are used hereinbefore and hereinafter: AcOHacetic acid AMBPA 3-amino-4-methylaminobenzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide CDI 1,1′-carbonyldiimidazole DIPEAdiisopropylethylamine EE ethyl acetate EtOH ethanol HCl hydrochloricacid MIBK methylisobutylketone (4-methyl-2-pentanone) MtBEmethyl-tert-butylether NaOH sodium hydroxide NMP N-methylpyrrolidone PPApropanephosphonic anhydride PTSA p-toluenesulphonic acid RT roomtemperature THF tetrahydrofuran decomp. decomposition

Example 1 Preparation of 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-aniline (1)

Variant 1:

(1A)

In the reaction vessel are placed 118.6 g (1 mol) 4-aminobenzonitrileand 68.9 g (0.65 mol) sodium carbonate in 500 ml of ethanol and 100 mlof water and the mixture is heated to 60° C. 76.4 g (1.1 mol)hydroxylamine-hydrochloride, dissolved in 100 ml of water, are slowlyadded dropwise to this suspension.

The mixture is subsequently stirred overnight at 60° C. During coolingto 0-5° C. the substance is precipitated, filtered off and washedseveral times with a total of 150 ml cold water and 100 ml cold ethanol.Finally the mixture is washed with 50 ml MtBE and 178.4 g moist productare obtained. This is dried at 35° C. in vacuo.

Yield: 135.4 g light beige substance (89.5% of theory), melting point:from 169.5° C. (decomp.); purity: >98% HPLC peak area

(1B)

25.02 g (0.46 mol) sodium methoxide are added batchwise to a suspensionof 60.5 g (1A) (0.4 mol) in 400 ml of ethanol at 70-75° C. and rinsedwith 20 ml of ethanol. After 15 min stirring 47.25 g (0.4 mol) diethylcarbonate are added dropwise. After 3 hours' reaction the mixture iscooled to 40° C. and the ethanol is distilled off at 120 mbar and 40° C.A dark residue is obtained. This is dissolved at 40-45° C. in 350 ml ofwater and after heating to 70° C., first adjusted to pH 11 by the slowaddition of semi-conc. sodium hydroxide solution; then to pH 5.5 byacidifying with conc. hydrochloric acid, and slowly cooled. The solutiongoes into a suspension, which is filtered and washed several times witha total of 150 ml cold water and 50 ml of ethanol. 88.7 g moistsubstance are obtained, which is dried at 35° C. in vacuo.

Yield: 62 g dark substance (87.5% of theory); melting point: from 178°C. (decomp.); purity: >98% HPLC peak area

Variant 2:

(1A)

In the reaction vessel are placed 41.3 g (0.35 mol) 4-aminobenzonitrileand 36.5 g (0.53 mol) hydroxylamine-hydrochloride in 175 ml of ethanoland the mixture is heated to 60° C. 170.1 g (0.53 mol) sodium ethoxidesolution (˜21% in ethanol) are slowly added dropwise to this suspension.

The mixture is subsequently stirred overnight at 60° C. During coolingto 0-5° C. the substance is precipitated, filtered off and washedseveral times with a total of 70 ml cold ethanol. Approx. 86 g moistproduct are obtained. This is further processed directly.

(1B)

32 g (0.35 mol) dimethyl carbonate are added to a suspension of 86 g(1A) in 270 ml of ethanol. At 65-75° C., 125 g (0.38 mol) sodiumethoxide solution (˜21% in ethanol) are added and rinsed with 20 ml ofethanol.

After 3 hours' reaction the mixture is cooled to 40° C. and the ethanolis distilled off at 120 mbar and 40° C. A dark residue is obtained. Thisis dissolved at 40-45° C. in 280 ml of water and after heating to 70° C.adjusted first to pH 11 by the slow addition of semi-conc. sodiumhydroxide solution; then to pH 3-4 or preferably to pH 2-3 by acidifyingwith conc. hydrochloric acid and slowly cooled. The solution goes into asuspension, which is filtered and washed several times with a total of50 ml cold water and 20 ml of ethanol. Approx. 88 g moist substance areobtained, which is dried at max. 50° C. in vacuo.

Yield: 48 g beige substance (77.5% of theory); melting point: from 178°C. (decomp.); purity: >98% HPLC peak area

Example 2 Preparation of2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid (2)

Variant 1:

(2A)

At ambient temperature 83.5 g (0.5 mol) ethyl bromoacetate are meteredinto a suspension of 70.86 g (0.4 mol) (1B) and 26.5 g (0.25 mol) sodiumcarbonate in 600 ml of water/isopropanol and stirred overnight. Thereaction mixture is reddish-brown to orange. The suspension cooled to 0°C. is suction filtered, washed in several batches with 300 ml of waterand 150 ml of ethanol (106 g moist light-brown substance) and dried at35° C. in vacuo.

Yield: 92.44 g brownish substance (87.7% of theory) melting point: from186.1° C. (decomp.); purity: >98% HPLC peak area

(2B)

The ester (2A) (86.9 g; 0.33 mol) thus obtained is suspended in 400 mlof water and at RT 120 g of 45% NaOH are slowly added dropwise. Thesuspension goes into solution and is reddish (pH 12.5). It is heated to60° C. and saponified for 1 h. The solution obtained is combinedbatchwise with HCl (37% or preferably with conc. HCl), until pH 5 isobtained. It is cooled to 0° C. The solid is suction filtered and washedin several batches with a total of 400 ml cold water as well as 40 mlcold ethanol and MtBE. 81.4 g moist dark substance are obtained. It isdried at 35° C. in vacuo.

Yield: 76.7 g substance (98% of theory) melting point: from 193° C.(decomp.) purity: >99% HPLC peak area

Variant 2:

(2A)

At 45° C. 60.2 g (0.36 mol) ethyl bromoacetate are metered into asuspension of 53.2 g (0.3 mol) (1B) and 19.1 g (0.18 mol) sodiumcarbonate in 500 ml of water/ethanol (90:10 to 95:5) and optionallystirred overnight. The reaction mixture is reddish-brown to orange. Thesuspension cooled to 0° C. is suction filtered, washed in severalbatches with 100 ml of ethanol and dried at max. 50° C. in vacuo.

Yield: 69.5 g brownish-beige substance (87.7% of theory); melting point:from 186.1° C. (decomp.); purity: >98% HPLC peak area

(2B)

The ester (2A) (86.9 g; 0.33 mol) thus obtained is suspended in 400 mlof water or preferably ethanol/water (1:1) and at RT 120 g of 45% NaOHare slowly added dropwise. The suspension goes into solution and isreddish (pH 12.5). It is heated to ˜60° C. and saponified for 1 h. Thesolution obtained is combined batchwise with HCl (37% or preferably withconc. HCl), until a pH 3 is obtained. It is cooled to 0° C. The solid issuction filtered and washed in several batches with a total of 400 mlcold water as well as 40 ml cold ethanol. 81.4 g moist substance areobtained. It is dried at 35° C. in vacuo.

Yield: 76.7 g substance (98% of theory) melting point: from 193° C.(decomp.) purity: >99% HPLC peak area

Example 3 Preparation of 3-amino-4-methylaminobenzoicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (AMBPA) (3)

Variant A: Pd/C 5%

150 g (0.4 mol) 4-methylamino-3-nitrobenzoicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide, 12 g 5% palladium oncharcoal catalyst and 627 ml of ethyl acetate are placed in ahydrogenating autoclave. The mixture is hydrogenated under a hydrogenatmosphere of 3-4 bar at 35-55° C. until the hydrogen uptake is constant(1-2 h). After cooling to 20° C. the hydrogenating solution is filteredoff from the catalyst and evaporated down in vacuo using the rotaryevaporator. The residue is taken up in 650 ml isopropanol, distilleddown to half the original volume and cooled to 5-10° C. After 4 h theresulting suspension is filtered, and the precipitate thus isolated iswashed batchwise with a total of 100 ml isopropanol. The solid obtainedis dried in the vacuum dryer at 50° C.

Yield: 114.2 g (corr. 83% of theory)

Variant B: Pd/C 10%

25 g (0.07 mol) 4-methylamino-3-nitrobenzoicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide, 2.5 g 10% palladiumon charcoal catalyst and 83 ml of ethyl acetate are placed in ahydrogenating autoclave. The mixture is hydrogenated under a hydrogenatmosphere of 3-4 bar at 50° C. until the hydrogen uptake is constant(4-5 h). After cooling to 20° C. the hydrogenating solution is filteredoff from the catalyst and evaporated down in vacuo using the rotaryevaporator. The residue is dissolved warm in a little ethyl acetate andcombined with 68 ml of toluene. After cooling to 5° C. the mixture isleft for 1 h with stirring, then the precipitate is filtered off andwashed with toluene. The product obtained is dried at 40° C. in thevacuum dryer.

Yield: 20.9 g (corr. 91% of theory)

Example 4 Preparation of1-methyl-2-[N-[4-(1,2,4-oxadiazol-5-on-3-yl)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (4)

Variant A: CDI as Coupling Reagent

11.35 g (70 mmol) 1,1′-carbonyldiimidazole are suspended in 100 ml THFand heated to 50° C. 14.23 g (60.5 mmol) (2B) are added batchwise. 17.1g (50 mmol) AMPBA are dissolved in 37 ml THF with heating to 50° C.

After approx. 90 min the suspension is metered into the solution ofAMPBA and rinsed with 20 ml THF.

The reaction mixture is stirred for approx. 18 h and subsequently, afterthe addition of 100 ml acetic acid, refluxed, so that the THF isdistilled off. After approx. 1 h the mixture is combined with 400 ml ofwater and stirred.

The solution is cooled, the pink solid substance precipitated isfiltered off and washed with 20 ml of water in 2 batches and dried at amaximum of 50° C. in vacuo.

Yield: 24.8 g substance (75% of theory); melting point: from 167° C.with decomp. (DSC); purity: >95% HPLC peak area

Variant B: PPA as Coupling Reagent

34.2 g (0.1 mol) AMBPA, 27.5 g (0.12 mol) (2B) and 30.3 g (0.23 mol)DIPEA are placed in 170 ml THF and cooled to somewhat below ambienttemperature.

Now 85 g (0.13 mol) PPA (as ˜50% solution in ethyl acetate) are meteredin. The mixture is stirred for another 90 min and then the solvent isdistilled off. Towards the end 73.5 g acetic acid are added and themixture is heated to an internal temperature of 90° C.

Then 400 ml of ethanol or preferably 400 ml of ethanol/water (approx.85:15) and kieselguhr filtering adjuvant (e.g. Clarcel®) are added andthe mixture is filtered hot.

The solution is cooled, the solid substance precipitated is filtered offand washed in 2 batches with 50 ml of ethanol and dried at max. 50° C.in vacuo.

Yield: 56 g substance (85% of theory); melting point: from 167° C. withdecomp. (DSC); purity: >95% HPLC peak area

Variant C: Pivaloyl Chloride as Coupling Reagent

96 g (0.41 mol) (2B) are suspended in 250 ml NMP and 550 ml THF at 0° C.The thin suspension is combined successively with 48 g (0.4 mol)pivaloyl chloride and 52 g (0.4 mol) DIPEA and stirred for 30 minutes.Then 125 g (0.36 mol) AMBPA dissolved in 800 ml acetic acid are addedand the reaction mixture is refluxed for 3 h. THF is distilled off undera gentle vacuum and 1600 ml of water are metered in with heating. Thesolid is isolated at 5° C., washed with 550 ml of water and driedovernight in the circulating air dryer at max. 50° C.

Yield: 183 g (76%) purity: >95% HPLC peak area

Example 5 Preparation of1-methyl-2-[N-[4-amidinophenyl]-amino-methyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (5A)

Variant A: Hydrogenation of (4) in Ethanol

37.3 g (56.4 mmol) (4) are dissolved in 900 ml of ethanol and after theaddition of 10 ml acetic acid the mixture is hydrogenated at 2 barhydrogen with 4 g water-moistened 10% Pd/C at RT. The catalyst isfiltered off and 17 g (89.4 mmol) PTSA, dissolved in 180 ml of ethanolare added. The tosylate of (5A) is precipitated, filtered off and washedin several batches with 150 ml of ethanol.

Moist substance is obtained, which is dried in vacuo at 35° C.

Yield: 34.5 g light beige substance (91.3% of theory); melting point:187° C. (DSC); purity: >98% HPLC peak area.

Variant B: Hydrogenation of (4) in Ethanol/Water

37.3 g (56.4 mmol) (4) are dissolved in 400 ml of ethanol/water (90:10)and hydrogenated at 4 bar hydrogen with 4 g water-moistened 10% Pd/C at60° C. The catalyst is filtered off and 11.5 g (60.6 mmol) PTSA areadded. During evaporation the tosylate of (5A) is precipitated. Thesuspension is cooled, the substance is filtered off and washed inseveral batches with 150 ml of ethanol/water.

Moist substance is obtained, which is dried in vacuo at 35° C.

Yield: 33.7 g light beige substance (89% of theory); melting point: 187°C. (DSC); purity: >98% HPLC peak area.

Variant C: Hydrogenation of (4) in THF/Water

30.0 g (45.3 mmol) (4) are dissolved in 90 ml THF/water (1:1) at ambienttemperature, combined with 4 g water-moistened 10% Pd/C and hydrogenatedat 4 bar and 60° C. The catalyst is filtered off, washed with approx. 40ml THF/water (1:1) and the filtrate is fed into the next step withoutworking up or is isolated as described above by the addition of 13.6 g(72 mmol) PTSA, dissolved in 100 ml of water, and cooling.

Example 6 Preparation of1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (6B)

The compound obtained according to Example 4 is reacted withn-hexylchloroformate in the presence of a base in known manner.

Variant A: Acylation of (5A) in Acetone/Water

55 g (81.9 mmol) (5A), dissolved in 437 ml acetone and 273 ml of water,are combined with 16.4 g (99.6 mmol) n-hexylchloroformate in thepresence of 34 g (246 mmol) potassium carbonate at a temperature ofapprox. 15° C. After the end of the reaction the precipitated product isfiltered off and washed with acetone/water. If necessary it may bedissolved again in approx. 270 ml acetone with heating and subsequentlyfiltered. After filtration the substance is crystallised again byaddition of 220 ml of water.

The isolated substance is dried at 45° C. in vacuo.

Yield: 42-48 g (82-94%)

Variant B: Acylation of (5A) in Acetone/Water with Phase Separation

50 g (74.4 mmol) 5A, suspended in 380 ml acetone and 248 ml of water,are combined with 13.48 g (81.9 mmol) n-hexylchloroformate in thepresence of 63 g (447 mmol) potassium carbonate at a temperature ofapprox. 15° C. After the end of the reaction the suspension is heated toabout 50° C. After the phase separation the aqueous phase is discardedand the acetone is replaced by 450 ml butyl acetate. The aqueous phasethen separated off is discarded and the organic phase is washed withwater in several batches. After the organic phase has been dried byazeotropic distillation the product is crystallised at approx. 60-80°C., isolated and washed with butyl acetate. The product is dried at 60°C. in vacuo.

Yield: 47 g (87%) purity: >99% HPLC peak area

Variant C: Acylation of (5A) in Acetone/Water with Phase Separation inon the kg Scale

40 Kg (59.5 mol) 5A are suspended together with 50.4 kg (365 mol)potassium carbonate in 300 1 acetone and 200 1 water. 10.8 kg (65.6 mol)n-hexylchloroformate are metered into the suspension within 1 h atapprox. 15° C. and after 30 min stirring the suspension is heated to 50°C. After separation of the aqueous phase acetone is replaced by butylacetate. The aqueous phase that separates off is discarded and theorganic phase is extracted twice with water. After the organic phase hasbeen dried by azeotropic distillation the product 6B is crystallised,isolated and washed with butyl acetate. The product is dried at 60° C.in vacuo.

Yield: 30.5 kg (82%) purity: >99% HPLC peak area

Example 7 Preparation of1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (6B) from1-methyl-2-[N-[4-(1,2,4-oxadiazol-5-on-3-yl)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (4)

60 g (91 mmol)1-methyl-2-[N-[4-(1,2,4-oxadiazol-5-on-3-yl)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (4) are hydrogenatedwith 3.0 g 10% palladium on charcoal (moistened with water) in 126 mlTHF and 54 ml of water at 40° C. under 4 bar excess hydrogen pressurefor 25 min. The hydrogenation solution is filtered and the filter iswashed with 75 g THF/water (7:3). The filtrate is combined successivelywith 56 ml THF, 260 ml of water and batchwise with 75.2 g (544 mmol)potassium carbonate at ambient temperature. Then 14.2 g (86 mmol) ofn-hexylchloroformate are metered in over 40 min. After the conversionlevel has been checked a further 1.2 g (7.3 mmol) n-hexylchloroformateare metered in, so that all the starting material is reacted. Thesuspension is heated to approx. 45° C. A clear two-phase mixture isformed. The aqueous phase is discarded and the THF is largely distilledoff. 150 ml acetone are added to the suspension, it is heated to 50° C.and filtered clear. The filter is rinsed with 100 ml acetone. Thefiltrate is cooled to ambient temperature and the product isprecipitated by the slow addition of 100 ml of water. The moist productis washed with 150 ml acetone/water (1:1) and 150 ml of water and driedin vacuo.

Yield: 56.9 g (94%) HPLC-purity: >98.8%

Example 8 Preparation of1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide mesylate (7)

100 g (0. 16 mol) of the compound (6B) are dissolved in 890 ml acetonewith heating and combined with a solution of 15 g (0.16 mol)methanesulphonic acid in 200 ml acetone.

The solution is filtered and after the addition of 77 ml acetone cooledto approx. 20° C.

The precipitated product is isolated and washed with acetone.

Then the mixture is dried at max. 50° C. in the vacuum dryer.

Yield: 90-98% (103-113 g)

Example 9 Preparation of1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]-amino-methyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide mesylate (7) from1-methyl-2-[N-[4-amidinophenyl]-amino-methyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (5A)

In the reaction vessel 50.0 g (74.4 mmol) 5A and 63.0 g (446.6 mmol)potassium carbonate are suspended in 380 ml acetone and 248 ml of waterand at 20° C. 13.48 g (81.9 mmol) of n-hexylchloroformate are metered inwithin 1 h. After 30 min further reaction the suspension is heated toapprox. 50° C. A clear two-phase mixture is formed, into which another0. 12 g (0.7 mmol) n-hexylchloroformate are metered after the conversionlevel has been checked, so that all the starting material is reacted.The aqueous phase is separated off, the organic phase is filtered clearand the filter is washed with 50 ml acetone. Under a slight vacuum 300ml acetone are distilled off and replaced by 250 ml MIBK. The aqueousphase that settles out is separated off and the organic phase isextracted at 50-60° C. with 50 ml of water. Then 300 ml solvent aredistilled off and replaced by 500 ml acetone. The reaction solution iscooled to 30-36° C., 7 seed crystals are added (obtained for examplefrom an earlier reaction according to Example 7 or according to themethod described in Example 3 of WO 03/074056) and a previously preparedsolution of 6.44 g (67 mmol) methanesulphonic acid in 50 ml acetone isadded dropwise. The suspension is stirred for 20 min, the product isisolated by filtration and washed with 300 ml acetone. The isolatedsubstance is dried at 45° C. in vacuo.

Yield: 48.0 g (89%) purity: >99% HPLC peak area

1. Process for preparing an optionally substituted4-benzimidazol-2-ylmethylamino)-benzamidine, characterised in that (a)an optionally correspondingly substituted diaminobenzene is condensedwith 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid and (b)the product thus obtained is hydrogenated.
 2. The process as recited inclaim 1 further comprising carbonylating the amidino group without firstisolating the product of hydrogenation.
 3. Process according to claim 1for preparing an optionally substituted4-benzimidazol-2-ylmethylamino)-benzamidine of formula (I)

wherein R¹ denotes a C₁₋₆-alkyl or C₃₋₇-cycloalkyl group, R² (i) denotesa C₁₋₆-alkyl group, a C₃₋₇-cycloalkyl group optionally substituted by aC₁₋₃-alkyl group, while the C₁₋₃-alkyl group may additionally besubstituted by a carboxyl group or by a group which may be converted invivo into a carboxy group, or (ii) denotes an R²¹NR²² group, wherein R²¹denotes a C₁₋₆ alkyl group which may be substituted by a carboxy, C₁₋₆alkoxycarbonyl, benzyloxycarbonyl, C₁₋₃-alkylsulphonylaminocarbonyl,phenylsulphonylaminocarbonyl, trifluorosulphonylamino,trifluorosulphonylaminocarbonyl or 1H-tetrazolyl group, a C₂₋₄-alkylgroup substituted by a hydroxy, phenyl-C₁₋₃-alkoxy,carboxy-C₁₋₃-alkylamino, C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylamino,N-(C₁₋₃-alkyl)-carboxy-C₁₋₃-alkylamino orN-(C₁₋₃-alkyl)-C₁₋₃-alkoxycarbonyl-C₁₋₃-alkylamino group, while in theabove-mentioned groups the carbon atom in the α position to the adjacentnitrogen atom cannot be substituted, or a piperidinyl group optionallysubstituted by a C₁₋₃-alkyl group, and R²² denotes a hydrogen atom, aC₁₋₆-alkyl group, a C₃₋₇-cycloalkyl group optionally substituted by aC₁₋₃-alkyl group, or a C₃₋₆-alkenyl or C₃₋₆-alkynyl group, while theunsaturated moiety may not be linked directly to the nitrogen atom ofthe R²¹NR²² group, a phenyl group optionally substituted by a fluorine,chlorine or bromine atom, by a C₁₋₃-alkyl or C₁₋₃-alkoxy group, or abenzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl orimidazolyl group optionally substituted by a C₁₋₃-alkyl group, or R²¹and R²² together with the nitrogen atom between them denote a 5- to7-membered cycloalkyleneimino group optionally substituted by a carboxyor C₁₋₄-alkoxycarbonyl group, to which additionally a phenyl ring may befused, and R³ denotes a hydrogen atom, a C₁₋₉-alkoxycarbonyl,cyclohexyloxycarbonyl, phenyl-C₁₋₃-alkoxycarbonyl, benzoyl,p-C₁₋₃-alkyl-benzoyl or pyridinoyl group, while the ethoxy moiety in the2 position of the above-mentioned C₁₋₉-alkoxycarbonyl group mayadditionally be substituted by a C₁₋₃-alkylsulphonyl or2-(C₁₋₃-alkoxy)-ethyl group, while in step (a) a phenyldiamine offormula (II)

 wherein R¹ and R² have the meanings given for formula (I), is reactedwith 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, theresulting product of formula (III)

 wherein R¹ and R² have the meanings given for formula (I), ishydrogenated in step (b)i), and subsequently, without any priorisolation of the hydrogenation product, the compound of formula (I) thusobtained wherein R³ denotes hydrogen is optionally reacted in step(b)ii) with a compound of formula (IV)R³—X  (IV)  wherein R³ has the meaning given for formula (I), and Xdenotes a suitable leaving group.
 4. Process according to claim 3, forpreparing a compound of formula (I), wherein R¹ denotes a C₁₋₃-alkylgroup, R² denotes an R²¹NR²² group, wherein R² denotes a C₁₋₃ alkylgroup which may be substituted by a carboxy, C₁₋₃ alkoxycarbonyl, andR²² denotes a hydrogen atom, a C₁₋₃-alkyl group, a pyridinyl groupoptionally substituted by a C₁₋₃-alkyl group, and R³ denotes a hydrogenatom or a C₁₋₈-alkoxycarbonyl group.
 5. Process according to claim 4,for preparing the compound of formula (I), wherein R¹ denotes a methylgroup, R² denotes an R²¹NR²² group, wherein R²¹ denotes an ethyl groupwhich is substituted by an ethoxycarbonyl group, and R²² denotes apyridin-2-yl group, and R³ denotes an n-hexyloxycarbonyl group. 6.Process according to claim 3, characterised in that the compound offormula (I) thus obtained is subsequently converted into aphysiologically acceptable salt.
 7. Process according to claim 6,characterised in that the physiologically acceptable salt is themethanesulphonate.
 8. Process for preparing a salt of an optionallysubstituted 4-(benzimidazol-2-ylmethylamino)-benzamidine, wherein (a) anoptionally correspondingly substituted diaminobenzene is condensed with2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, (b) theproduct thus obtained is hydrogenated, and (c) the amidino group iscarbonylated.
 9. The process according to claim 8 further comprisingisolating the desired salt without prior isolation of the product of thecarbonylation
 10. Process according to claim 8 for preparing a salt ofan optionally substituted 4-(benzimidazol-2-ylmethylamino)-benzamidineof formula (I)

wherein R¹ to R³ are defined as in claim 3, comprising the followingsteps: (a) reacting a phenyldiamine of formula (II)

 wherein R¹ and R² have the meanings given for formula (I), with2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid, (b)hydrogenating the product of formula (III) thus obtained

 wherein R¹ and R² have the meanings given for formula (I), and (c) i)reacting the compound of formula (I) thus obtained, wherein R³ denoteshydrogen, with a compound of formula (IV)R³—X  (IV)  wherein R³ has the meaning given for formula (I) and Xdenotes a suitable leaving group, and ii) precipitating the desired saltof the compound of formula (I) thus obtained, without previouslyisolating the carbonylation product.
 11. Process according to claim 10,for preparing a salt of a compound of formula (I), wherein R¹ denotes aC₁₋₃-alkyl group, R² denotes an R²¹NR²² group, wherein R²¹ denotes aC₁₋₃ alkyl group which may be substituted by a carboxy, C₁₋₃alkoxycarbonyl, and R²² denotes a hydrogen atom, a C₁₋₃-alkyl group, apyridinyl group optionally substituted by a C₁₋₃-alkyl group, and R³denotes a hydrogen atom or a C₁₋₈-alkoxycarbonyl group.
 12. Processaccording to claim 11, for preparing a salt of the compound of formula(I), wherein R¹ denotes a methyl group, R² denotes an R²¹NR²² group,wherein R²¹ denotes an ethyl group which is substituted by anethoxycarbonyl group, and R²² denotes a pyridin-2-yl group, R³ denotesan n-hexyloxycarbonyl group and the counter-ion is methanesulphonate.13. Process according to claim 8, characterised in that the condensationof step (a) is carried out in the presence of an inert diluent and awater-binding agent.
 14. Process according to claim 8, characterised inthat the hydrogenation of step (b) or (b)i) is carried out in thepresence of an inert diluent and a hydrogenation catalyst.
 15. Processaccording to claim 8, characterised in that in order to prepare2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid2-[4-(1,2,4-oxadiazol-5-on-3-yl)-aniline is reacted with a 2-haloaceticacid ester in the presence of a weak base, and the2-[4-(1,2,4-oxadiazol-5-on-3-yl)-phenylamino]-acetic acid ester obtainedis saponified.
 16. Process according to claim 8, characterised in thatin order to prepare 2-[4-(1,2,4-oxadiazol-5-on-3-yl)-aniline,4-aminophenyl-amidoxime is reacted with a dialkyl carbonate in thepresence of a base.